The focus of this renewal application is the continued development and application of a unique multiscale approach to study membranes and membrane-bound processes. The project involves the development of conceptual and computational methodologies for three interconnected regimes at three different scales, i.e., the continuum, mesoscopic, and atomistic scales. Generally speaking, these three regimes are separated by up to three orders-of-magnitude in their relevant length- and time-scales. In this project, new approaches will continue to be developed for each of the three regimes (especially at the challenging continuum and mesoscopic scales) and, importantly, they will be linked together in a multi-scale computational fashion. The resulting Specific Aims will involve: (1) the development of a multi-scale simulation approach for the description of membrane bound proteins and peptides, with specific applications to mechanosensitive channels that are gated in response to external applied stress, BAR domain-containing proteins which are believed to induce membrane curvature, and neuroactive peptides that affect ion channel function; (2) the coupling of the mesoscopic simulation component to NMR measurements in order to both validate the next generation mesoscopic model and to unravel the origins of complex, experimentally observed mesoscopic and atomistic-level membrane motions; and (3) the development of a continuum-level description of lipid domain formation and dynamics coupled to large-scale membrane motion and deformation, through a novel synthesis of field theory with computational continuum mechanics. The overarching long term goal of this project is to provide a new multi-scale, physics-based approach for the computational study of biologically important membrane and membrane-bound processes. [unreadable] [unreadable]